The mechanisms by which alcohol exerts deleterious effects on human memory are still poorly understood. Recent data indicate that alcohol blocks experience-dependent gene activation in the hippocampus, a brain structure which plays a critical role in the acquisition of memory. The goal of the present proposal is to test whether alcohol suppresses memory because of its selective inhibition of hippocampal activity and to investigate the neurochemical and pharmacological mechanisms of this inhibition. The first specific aim of the proposed research is to investigate the effects of acute alcohol intoxication on hippocampus-dependent and -independent learning and experience-induced neural activity. A series of behavioral studies using the contextual conditioning paradigm in rats will determine the selectivity of suppressive effects of ethanol on hippocampal functions and dissect the sensory specificity of these effects of alcohol. Experiments using expression of immediate early genes (IEGs) as an activity-dependent neuronal maker will address whether alcohol~s effects on hippocampal activity, determined by behavioral means, are accompanied by parallel changes in hippocampal gene expression. The second specific aim of this study is to investigate the neurochemical mechanisms leading to alcohol's suppression of hippocampus-dependent learning and neural activity. Experiments with pharmacological agents will determine whether GABAA receptor agonist and antagonists can modulate alcohol effects on hippocampus-dependent forms of fear conditioning and experience- induced hippocampal activity. Double-labeling studies will establish the neurotransmitter nature of hippocampal neurons in which alcohol changes experience-induced IEG expression. Western blotting and immunohistochemical analysis will be performed to assess what second messenger system mediates alcohol~s effects on hippocampal IEG expression and memory. Finally, the DNA binding activity of transcription factor complexes from hippocampus after learning and alcohol intoxication will be investigated in a series of band-ship experiments. Taken together, these studies will provide valuable insight at several levels of analysis of alcohol~s action on cognitive functions and eventually allow to start understanding of the mechanisms involved in alcohol-induced amnesia.